Adenosine acts extracellularly via activation of specific membrane-bound receptors called P1-purinoceptors. These adenosine receptors can be divided into four subclasses, A1, A2A, A2B and A3 receptors. All four classes are coupled to the enzyme adenylate cyclase. Activation of the adenosine A1 and A3 receptors leads to an inhibition of adenylate cyclase, while activated A2A and A2B receptors stimulate adenylate cyclase. The adenosine receptors are ubiquitously distributed throughout the body. As a consequence, ligands need to be highly selective in their action with respect to receptor subtype and tissue to be of therapeutic value.
Receptor subtype selectivity can be achieved by substituting the adenosine molecule. For example modification at the N6 position of adenosine is well tolerated. N6-substituents such as cyclopentyl enhance adenosine A1 receptor selectivity relative to the other subtypes,1,2 while a 3-iodobenzyl group induces adenosine A3 receptor selectivity.3-5 Bulky substituents such as (ar)alkylamino,6 alkylidenehydrazino7 and alkynyl,8 at the 2-position of the adenine moiety yield selectivity for the adenosine A2A receptor compared to A1. Only more recently, the 2-(ar)alkynyl adenosine derivatives have been evaluated at the adenosine A3 receptor. Quite surprisingly, some of these compounds appeared to be selective for the adenosine A3 receptor rather than for A2A.9,10 
Tissue selectivity is often the result of partial agonism, which may reduce the extent of side effects.11,12 Due to differences in receptor-effector coupling in various tissues selectivity of action in vivo may be achieved. Partial agonists for the adenosine receptors may be of use as antipsychotic drugs, e.g., via stimulation of the adenosine A2A receptor that leads to inhibition of dopamine D2 receptors in the basal ganglia,13,14 and as cardio- and cerebroprotective agents via the adenosine A3 receptor when chronically administered.15,16.